The protein variously known as ST2, T1, or Fit-1 is a member of the immunoglobulin superfamily. This superfamily, defined by certain conserved amino acid sequences, comprises proteins exhibiting diverse functions that include antigen recognition, cell adhesion, and signal transduction (reviewed in Williams and Barclay, Annu. Rev. Immunol. 6:381, 1988).
Cloning of murine T1 cDNA was described by Klemenz et al. (Proc. Natl. Acad. Sci. USA 86:5708, 1989). The predicted amino acid sequence of the T1 protein was reported to be similar to that of human carcinoembryonic antigen, a tumor marker that is a member of the immunoglobulin gene superfamily. The encoded amino acid sequence included an N-terminal signal peptide, but no transmembrane region, suggesting that the T1 protein was secreted rather than membrane-bound.
Cloning of cDNA encoding the same murine protein, which was designated ST2, was reported by Tominaga (FEBS LETTERS 258:301, 1989). The encoded ST2 protein was determined to be a member of the immunoglobulin superfamily, and to be especially similar to the extracellular domain of the mouse type I interleukin- 1 receptor.
DNA encoding a membrane-bound form of the mouse ST2 protein has been isolated and designated ST2L (Yanagisawa et al., FEBS LETTERS 318:83, 1993). The encoded protein contains the signal peptide and extracellular domain of the previously-identified ST2 protein, but comprises additional 3' sequence encoding a transmembrane region and a cytoplasmic domain. The amino acid sequences of ST2L and murine type I IL-1 receptor were found to be 28% identical over the whole protein, 25% identical in the extracellular domains, and 38% identical in the cytoplasmic domains. Regarding murine type II IL-1 receptor, the amino acid sequence of the extracellular domain was 23% identical to that of ST2/ST2L, while the cytoplasmic domain exhibited no significant homology to the cytoplasmic domain of ST2L.
Human ST2 cDNA and genomic clones have been isolated (Tominaga et al. Biochimica et Biophysica Acta 1171:215, 1992). The amino acid sequence encoded by the cDNA includes a signal peptide but apparently lacks any transmembrane region. No membrane-bound human ST2 protein was reported. The DNA and predicted amino acid sequences of human ST2 were said to be substantially similar to those of overlapping regions of human interleukin-1 receptor (both type I and type II; McMahan et al., EMBO J. 10:2821., 1991 ); the B16R protein of vaccinia virus (Goebel et al., Virology 179:247, 1990), Cek 2 of Drosophila (a protein tyrosine kinase; Pasquale, Proc. Natl. Acad. Sci. USA 87:5812, 1990); and klg (a chicken kinase-like protein; Chou and Hayman, Proc. Natl. Acad. Sci. USA 88:4897, 1991).
Werenskiold (Eur. J. Biochern. 204:1041, 1992) further characterizes a recombinant secreted form of the murine T1 glycoprotein. The possibility that T1 plays a role in neoplastic transformation or cell proliferation was suggested.
DNAs encoding a membrane-bound form and a naturally occurring secreted (soluble) form of the rat homolog of the ST2 protein have been isolated (Bergers et al., EMBO J. 13:1176, 1994). The membrane-bound rat protein is most closely related to the type I IL-1 receptor. The two forms of the protein are expressed from different promoters, allowing differential regulation. Expression of the mouse gene in different tissues at various developmental stages was investigated. The mRNA encoding the membrane-bound form was found to be expressed more abundantly than mRNA for the secreted form in fetal liver and in adult lung and hematopoietic tissues. The transcript for the secreted form predominated in fibroblasts and mammary epithelial cells.
As discussed above, ST2 is structurally similar to interleukin-1 receptors. In addition, the St2 locus is very tightly linked to the II-lr1 and II-lr2 loci on mouse chromosome 1 (Tominaga et al., Biochimica et Biophysica Acta 1090: 1, 1991 ). Consequently, the hypothesis that interleukin-1 will bind to ST2 has been presented by several investigators (Tominaga et al., 1992, supra; Yanagisawa et al., 1993, supra; Bergers et al., supra). The search for a ligand for ST2 thus was initially focused on interleukin- 1.